ReviewChloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies
Introduction
If we want to further improve cancer cure rates, we need to understand the detailed control mechanism how anti-cancer therapeutics function in the context of cellular and molecular control pathways in normal and cancer cells. Furthermore, the limitation of drug concentrations used for therapy is a serious problem, mainly due to side effects. Thus, there is an urgent need for developing more effective cancer modalities with minimal side effects. Since cancer is caused by a complex chain of events, combinational modalities may provide a better response to cancer therapy (Cheng et al., 2008, Rosales-Hernandez et al., 2009).
A study of 68 newly approved drugs estimated that developing a single effective cancer drug takes an average of 15 years and US$800 million (DiMasi et al., 2003). One approach to overcome this enormous problem may be developing a new use of existing drugs. The renowned pharmacologist and Nobel laureate James Black said, “the most fruitful basis for the discovery of a new drug is to start with an old drug” (Chong and Sullivan, 2007). Since many existing drugs have been studied for their pharmacokinetics and safety profiles, and often have already been approved by regulatory agencies for human use, any newly identified use of them can be rapidly evaluated in phase II trials (DiMasi et al., 2003). Developing a known drug for another clinical purpose is termed “repurposing”. The efficacy and specificity of a known drug can also be improved by modifications of its chemical side chains and functional groups, which is termed “repositioning”.
Chloroquine is a well-known 4-aminoquinoline class of drug that is widely used for the prophylaxis treatment of malaria (Wiesner et al., 2003). Even after six decades of use, CQ still remains the drug of choice for malaria treatment because it is effective, low toxic to humans, and inexpensive (Breckenridge and Winstanley, 1997). Biochemical data suggest that this class of compounds enter acidic vacuoles of host cells, where they inhibit the growth of parasites by forming a complex with haematin (Dorn et al., 1995, Pandey et al., 2001, Sullivan et al., 1996). The anti-inflammatory property of CQ also makes it a useful agent for the treatment of rheumatoid arthritis (Augustijns et al., 1992, Titus, 1989), lupus erythematosus (Meinao et al., 1996) and amoebic hepatitis (Conan, 1948). Furthermore, CQ inhibits pro-inflammatory cytokine release into the blood stream, suggesting that it may have therapeutic benefits for chronic inflammation diseases as well as for relieving symptoms caused by bacteria-induced inflammation (Karres et al., 1998). Chloroquine is currently in clinical trials as an investigational anti-retroviral agent in humans with HIV-1/AIDS (Savarino et al., 2003, Savarino et al., 2006) and as a potential anti-viral agent against chikungunya fever (Savarino et al., 2007). In addition, CQ has been studied for its potential in the enhancement of radiation therapy (Beierwaltes et al., 1968, Zhao et al., 2005), chemotherapy, and combinational therapy for cancer ( Carew et al., 2006, Degtyarev et al., 2008, Hagihara et al., 2000, Hu et al., 2008). Our current review focuses on CQ and its analogs as enhancement agents for cancer therapies.
Section snippets
Discovery of CQ from quinine
In the 18th century, the first attempt of successful treatment of malaria was made by utilizing the bark of cinchona trees, which had been used for the treatment of fever since the beginning of the 17th century (Meshnick and Dobson, 2001). Subsequently, Pelletier and Caventou isolated the cinchona alkaloid active ingredient quinine (Fig. 1) and cinchonine from the crude extracts of cinchona bark (Pelletier and Caventou, 1820). Quinine was then widely used as an anti-malarial agent, replacing
The property of CQ
Chloroquine is usually prepared as a diphosphate salt of N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine, which is a diprotic weak base (pka1 = 8.1, pka2 = 10.2) that can exist in both charged (i.e., protonated) and uncharged (i.e., unprotonated) forms. An unprotonated CQ can diffuse freely and rapidly across the membranes of the cell and organelles. Once protonated, CQ may be “trapped” in the organelles such as the lysosomes since it can no longer freely diffuse out. This may be
Combined therapies with CQ and other cancer therapeutics
Combination of one or more therapeutic agents has been used to improve the outcome of cancer therapies (Chau and Cunningham, 2006, Faivre et al., 2006, Hennig et al., 2004, Hosoya et al., 1999). Although some of the combination therapies have been shown to improve overall patient survival, such treatments are often associated with an increase in toxicity and the potential for developing cross-resistance (Ocana et al., 2006, Thomsen and Kolesar, 2008). Thus, there is an urgent need for
Miscellaneous
Accumulating lines of evidence now suggest that the development of weak DNA-intercalating bioreductive compounds is an effective strategy to ensure DNA affinity high enough to produce toxicity yet low enough to permit efficient extravascular diffusion and penetration to hypoxic tumor tissue (Brown, 2000). Based on this strategy, Papadopoulou et al. (2000) synthesized a CQ derivative, 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NIPCQ, NSC709257, Fig. 6). The
Future directions
The lysosomotropic CQ is accumulated in the lysosomes, raises intra-lysosomal pH, and interferes with autophagosome degradation in the lysosomes. This unique property of CQ may be important for the enhancement of cell killing by cancer therapeutic agents in a variety of different tumors and genetic backgrounds (Amaravadi et al., 2007, Carew et al., 2006, Maclean et al., 2008, Zhao et al., 2005). Together, published data suggest that combined modalities of CQ with other therapeutics are very
Acknowledgements
The authors are grateful to Jane Vanderklift for her help in the editorial preparation of this manuscript. This work was supported by funds from the Canadian Breast Cancer Foundation (CBCF, Ontario Chapter), the Ontario Institute of Cancer Research/Cancer Care Ontario, and the Northern Cancer Research Foundation to H.L. V.R.S. thanks the Ontario Ministry of Research & Innovation for Postdoctoral Fellowship.
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